This proposal requests support for a Keystone Symposia meeting entitled Clinical and Molecular Biology of Acute and Chronic Traumatic Encephalopathies, organized by Sam Gandy, Steven T. DeKosky and Ann McKee, which will be held in Keystone, Colorado from February 26 - March 2, 2012. Acute traumatic brain injury (TBI) and its long-term neurodegenerative complications (known collectively as chronic traumatic encephalopathy, or CTE) are recognized increasingly as major public health issues, especially in the context of sports-related head injury and battlefield blast (military) exposure. Awareness of these issues has risen as neurological, psychiatric, and neurodegenerative phenomena are associated with professional athletes and with veterans returning from Iraqi and Afghan theaters. The physics of head injury, as well as the epidemiological and neuropsychiatric aspects of sports-related and blast-related syndromes, will be reviewed in the initial sessions of this 3-day meeting. Advances in functional neuroimaging and in the rapid and convenient determination of peptides and proteins in the cerebrospinal fluid and plasma will be reviewed in terms of their possible pathobiological significance as well as their identities as possible biomarkers. Later sessions will focus on the overlap between CTE and major neurodegenerative diseases, such as Alzheimer's disease (AD), frontotemporal dementia, and amyotrophic lateral sclerosis. CTE is associated with accumulation of aggregated proteins or protein fragments, including tau, TDP-43, the Alzheimer's amyloid precursor protein (APP), and the APP metabolite, amyloid-beta. New experimental therapeutics research targets the roles these abnormal protein structures play in injury severity and subsequent outcome. Abeta- lowering medications, currently in clinical trials for AD, improve outcome following acute brain trauma in rodent models, suggesting a pathway toward potential therapeutic interventions. Because apolipoprotein E (APOE) isotype is an important determinant of outcome from acute severe as well as mild repetitive TBI, this meeting coincides in time and venue with the Keystone Symposia meeting on ApoE, Alzheimer's and Lipoprotein Biology. Opening plenary sessions and an optional fourth day of sessions are available for those interested in learning more about basic biology and/or clinical interventions related to APOE. PUBLIC HEALTH RELEVANCE: Public awareness of the pathological consequences of traumatic brain injury (TBI) has been elevated by: 1) the prevalence of vehicular crashes and efforts to develop and perfect passenger safety features;2) recognition of the potential clinical significance of repetitive mild TBI associated with high-contact sports (initially boxing, and more recently, American football);and 3) modern warfare, especially blast injuries, with recognition of TBI as a "signature injury" currently affecting over half of those who survive blast exposure. The Keystone Symposia meeting on Clinical and Molecular Biology of Acute and Chronic Traumatic Encephalopathies will review and critically examine the epidemiology, molecular aspects and clinical spectrum of sports and military TBI, and its long-term neurodegenerative complications.